WARNINGS

WARNINGS

Anemia

HEMOLYTIC Anemia (hemoglobin <10 g/dl) was observed in APPROXIMATELY 10% of REBETOL/INTRON A- treated patients in clinical trials (see adverse reactions laboratory values - hemoglobin ). anemia occurred within 1-2 weeks of initiation of ribavirin therapy. because of this initial acute drop in hemoglobin, it is advised that complete blood counts (cbc) should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate.

The anemia associated with REBETOL/INTRON A therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease. Patients should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. (SeeDOSAGE AND ADMINISTRATION. ) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use combination REBETOL/INTRON A therapy. (SeeADVERSE REACTIONS. )

Similarly, patients with hemoglobinopathies (eg, thalassemia, sickle-cell anemia) should not be treated with combination REBETOL/INTRON A therapy.

Psychiatric

SEVERE PSYCHIATRIC ADVERSE EVENTS, INCLUDING DEPRESSION AND SUICIDAL BEHAVIOR (SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND SUICIDES) HAVE OCCURRED DURING COMBINATION REBETOL/INTRON A THERAPY AND WITH INTERFERON ALPHA MONOTHERAPY (including INTRON A therapy), BOTH IN PATIENTS WITH AND WITHOUT A PREVIOUS PSYCHIATRIC ILLNESS. REBETOL/INTRON A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders who report a history of severe depression, and physicians should monitor all patients for evidence of depression. In severe cases, therapy should be stopped and psychiatric intervention sought. In general, the adverse events resolve on cessation of therapy; however, adjunctive psychiatric medications may be required. (SeeADVERSE REACTIONS.)

Pulmonary

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, including fatality, have been reported during therapy with REBETOL/INTRON A. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination REBETOL/INTRON A treatment should be discontinued.

Other

REBETOL Capsule monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication.

Combination REBETOL/INTRON A therapy should be used with caution in patients with creatinine clearance <50 mL/min.

Ophthalmologic disorders have been reported with treatment with alpha interferons (including INTRON A therapy). Investigators using alpha interferons have reported the occurrence of retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction in rare instances. Any patient complaining of loss of visual acuity or visual field should have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual exam prior to initiation of combination REBETOL/INTRON A therapy is recommended in patients with diabetes mellitus or hypertension.

Combination REBETOL/INTRON A therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be controlled by medication.

PRECAUTIONS

Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). REBETOL/INTRON A therapy should be used with caution in patients with other autoimmune disorders.

There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant), exacerbating pre-existing psoriasis; therefore, combination REBETOL/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.

The safety and efficacy of REBETOL/INTRON A therapy has not been established in liver or other organ transplant patients, decompensated hepatitis C patients, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.

The safety and efficacy of REBETOL Capsule monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and REBETOL Capsules should not be used for these indications.

There is no information regarding the use of REBETOL Capsules with other interferons.

Pregnancy - including monthly monitoring for women of childbearing potential.

Carcinogenesis and Mutagenesis

Carcinogenicity studies with interferon alfa-2b, recombinant have not been performed because neutralizing activity appears in the serum after multiple dosing in all of the animal species tested.

Adequate studies to assess the carcinogenic potential of ribavirin in animals have not been conducted. However, ribavirin is a nucleoside analog that has produced positive findings in multiple in vitro and animal in vivo genotoxicity assays, and should be considered a potential carcinogen. Further studies to assess the carcinogenic potential of ribavirin in animals are ongoing.

Mutagenicity studies have demonstrated that interferon alfa-2b, recombinant is not mutagenic. Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 - 1 X the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominantlethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Impairment of Fertility

No reproductive toxicology studies have been performed using interferon alfa-2b, recombinant in combination with ribavirin. However, evidence provided below for interferon alfa-2b, recombinant and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effects produced by either agent alone will also be caused by the combination of the two agents. Interferons may impair human fertility. In studies of interferon alfa- 2b recombinant administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon. In addition, ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.

Fertile women and partners of fertile women should not receive combination REBETOL/INTRON A therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half- life (t 1/2 ) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (eg, 15 half-lives of clearance for ribavirin).

Combination REBETOL/INTRON A therapy should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin- induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 - 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 - 0.8 X the maximum human 24- hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin- induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

Animal Toxicology

Long- term studies in the mouse and rat (18-24 months; doses of 20-75 and 10 - 40 mg/kg/day, respectively estimated human equivalent doses of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 - 0.4 X the maximum human 24-hour dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin- treated rats.

Interferon alfa-2b, recombinant has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). There are no adequate and well-controlled studies in pregnant women.

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 X the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 X the maximum recommended human 24-hour dose of ribavirin).

Treatment and Posttreatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14-28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 X the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Women of childbearing potential should not receive combination REBETOL/INTRON A therapy unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple dose half-life (t 1/2 ) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with combination REBETOL/INTRON A therapy and for the 6-month posttherapy period (eg, 15 half-lives for ribavirin clearance from the body).

If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, physicians are encouraged to report such cases by calling (800) 727-7064.

Nursing Mothers

It is not known whether REBETOL and INTRON A are excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for nursing or to discontinue combination REBETOL/INTRON A therapy, taking into account the importance of the therapy to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.